• 제목/요약/키워드: First-in-human dose

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Interaction of HIV-1 Core p24 Antigen with Human Monocytic Cell Line THP1 Results in TNF-${\alpha}$ Dependent Secretion of Matrix Metalloproteinase-9

  • Sung, Ji-Hye;Yoo, Seung-Hee;Park, Hae-Kyung;Chong, Young-Hae
    • The Journal of the Korean Society for Microbiology
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    • v.35 no.1
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    • pp.9-18
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    • 2000
  • Immunological mechanisms involving the release of inflammatory factors by HIV-1 infected microglia in the brain have been implicated in the pathogenesis of HIV dementia (HIVD). Since the regulation of matrix metalloproteinases (MMPs) activity can be influenced by variety of inflammatory mediators, this study was undertaken to look for a correlation between the MMP-9 release and the production of TNF-${\alpha}$ in response to HIV-1 p24 in the human monocyte cell line THP-1 as a model for microglia. First, it was shown that HIV-l core p24 antigen induced THP-1 to secrete MMP-9 in a dose response manner while it elicited a little effect on MMP-2 release in human astroglial cell line T98G. Next, it was found that p24 induced THP-1 to secrete TNF-${\alpha}$ without prior differentiation into macrophages by phorbol myristate acetate (PMA) treatment. Furthermore, anti-TNF-${\alpha}$ neutralizing antibodies significantly blocked p24-induced MMP-9 release in a dose dependent manner. Our data indicate that p24 antigen induces monocytic MMP-9 release by triggering up-regulation of TNF-${\alpha}$ secretion.

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Assessment of Absorbed Dose of by Organ according to Thyroidal Uptake of Radioactive Iodine for Adult Korean Males (한국성인 남성을 대상으로 한 방사성옥소의 갑상선 섭취율에 따른 각 장기별 흡수선량 평가)

  • Kim, Junghoon;Lim, Changseon;Whang, Jooho
    • Progress in Medical Physics
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    • v.18 no.4
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    • pp.187-193
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    • 2007
  • In an effort to assess the internal absorbed dose of radionuclides that is suitable to Koreans' physiological characteristics, we asked 28 male Koreans to take $^{131}|$ orally, determined the thyroidal uptake and daily urination ratio, and assessed the absorbed dose by organ. As a result, first, 24 hours after administering, the average thyroidal uptake and the daily urination ratio registered 19.70% and 71.12%, respectively. Second, the whole body effective dose according to the thyroidal uptake calculated herein and the existing ICRP-suggested thyroidal uptake of 30% offered 1.464E-08 Sv and 2.189E-08 Sv, respectively, showing a 1.5 times difference. To evaluate the quantity of the absorbed dose of radioactive iodine, we can better reduce the error in assessing the body exposure dose by conducting measurement according to human races rather than depending on the existing ICRP data.

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Increasing injection frequency enhances the survival of injected bone marrow derived mesenchymal stem cells in a critical limb ischemia animal model

  • Kang, Woong Chol;Oh, Pyung Chun;Lee, Kyounghoon;Ahn, Taehoon;Byun, Kyunghee
    • The Korean Journal of Physiology and Pharmacology
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    • v.20 no.6
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    • pp.657-667
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    • 2016
  • Critical limb ischemia (CLI) is one of the most severe forms of peripheral artery diseases, but current treatment strategies do not guarantee complete recovery of vascular blood flow or reduce the risk of mortality. Recently, human bone marrow derived mesenchymal stem cells (MSCs) have been reported to have a paracrine influence on angiogenesis in several ischemic diseases. However, little evidence is available regarding optimal cell doses and injection frequencies. Thus, the authors undertook this study to investigate the effects of cell dose and injection frequency on cell survival and paracrine effects. MSCs were injected at $10^6$ or $10^5$ per injection (high and low doses) either once (single injection) or once in two consecutive weeks (double injection) into ischemic legs. Mice were sacrificed 4 weeks after first injection. Angiogenic effects were confirmed in vitro and in vivo, and M2 macrophage infiltration into ischemic tissues and rates of limb salvage were documented. MSCs were found to induce angiogenesis through a paracrine effect in vitro, and were found to survive in ischemic muscle for up to 4 weeks dependent on cell dose and injection frequency. In addition, double high dose and low dose of MSC injections increased vessel formation, and decreased fibrosis volumes and apoptotic cell numbers, whereas a single high dose did not. Our results showed MSCs protect against ischemic injury in a paracrine manner, and suggest that increasing injection frequency is more important than MSC dosage for the treatment CLI.

HPLC Determination and Pharmacokinetics of Endogenous Acetyl-L-Carnitine (ALC) in Human Volunteers Orally Administered a Single Dose of ALC

  • Kwon, Oh-Seung;Chung, Youn-Bok
    • Archives of Pharmacal Research
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    • v.27 no.6
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    • pp.676-681
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    • 2004
  • Acetyl-L-camitine (ALC), a naturally occurring endogenous compound, has been shown to improve the cognitive performance of patients with senile dementia Alzheimer's type, and to be involved in cholinergic neurotransmission. Because ALC is an endogenous compound, valida-tion of the analytical methods of ALC in the biological fluids is very important and difficult. This study was presented validation and correction for plasma ALC concentrations and pharmacok-inetics after oral administration of ALC to human volunteers. ALC concentrations in human plasma were corrected by subtracting the concentration of blank plasma from each sample. Precision and accuracy (bias %) for uncorrected ALC concentrations were below 2.6 and 6.5% for intra-days, and 4.0 and 9.4% for inter-days, respectively. Precision and accuracy (bias %)for corrected ALC concentrations were below 10.9 and 6.0% for intra-days, and 10.5 and 16.9% for inter-days, respectively. Quantitation limit was $0.1{\;}\mu\textrm{g}/mL$. After oral administration of a 500 mg ALC tablet to 8 healthy volunteers, the principle pharmacokinetic parameters were 4.2 h of the half-life$ (t_{1/2},{\beta})$, the area under the curve $(AUC_{0{\rightarrow}8){\;}of{\;}9.88{\;}\mu\textrm{g}{\cdot}h/mL$, and 3.1 h of the time ($T_{max}$) to reach $C_{max}$. This study first describes the pharmacokinetic study after oral admin-istration of a single dose of ALC in human volunteers.

Towards Quantitative Assessment of Human Exposures to Indoor Radon Pollution from Groundwater

  • Donghan Yu;Lee, Han-Soo
    • Journal of Korean Society for Atmospheric Environment
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    • v.17 no.E2
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    • pp.43-51
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    • 2001
  • A report by the national research council in the United States suggested that many lung cancer deaths each year be associated with breathing radon in indoor air. Most of the indoor radon comes directly from soil beneath the basement of foundations. Recently, radon released from groundwater is found to contribute to the total inhalation risk from indoor air. This study presents the quantitative assessment of human exposures to radon released from the groundwater into indoor air. At first, a three-compartment model is developed to describe the transfer and distribution of radon released from groundwater in a house through showering, washing clothes, and flushing toilets. Then, to estimate a daily human exposure through inhalation of such radon for an adult. a physiologically-based pharmacokinetic(PBPK) model is developed. The use of a PBPK model for the inhaled radon could provide useful information regarding the distribution of radon among the organs of the human body. Indoor exposure patterns as input to the PBPK model are a more realistic situation associated with indoor radon pollution generated from a three-compartment model describing volatilization of radon from domestic water into household air. Combining the two models for inhaled radon in indoor air can be used to estimate a quantitative human exposure through the inhalation of indoor radon for adults based on two sets of exposure scenarios. The results obtained from the present study would help increase the quantitative understanding of risk assessment issues associated with the indoor radon released from groundwater.

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A STUDY ON CHONDROGENIC POTENTIAL IN MANDIBULAR AND LIMB BUD MESENCHYMAL CELLS OF HUMAN EMBRYOS : A POSSIBLE ROLE OF PROTEIN KINASE C

  • Kook, Yoon-Ah;Kim, Eun-Cheol;Kim, Sang-Cheol
    • The korean journal of orthodontics
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    • v.26 no.6
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    • pp.667-676
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    • 1996
  • We have examined the in vitro stage-related chondrogenic potential of human mandibular and limb bud mesenchyme cells using micromass culture. Our results indicate that limb bud mesenchyme cells as early as stage 16 by Carnegie system (37 days), well before the initiation of in vivo chondrogenesis, have chondrogenic potential which is expressed in micromass culture. These results are correlated with stage-related chondrogenic potential of human limb bud in vivo as a result of Alcian blue staining. The proliferation of chondrogenic cells increased in the first 3 days after culture and then decreased. These results were correlated with the cell cycle analysis of which the number of $G_0^1/G_1$ phase increased markedly after 3 days of culture, while the percentage of cells in S phase was decreased. On the other hand, it was rarely differentiated in the mandible. We examined the effects of two PKC modulators such as phorbol 12-myristate 13-acetate (PMA), a potent activator of PKC, and staurosporine (STSN), an inhibitor of PKC. PMA inhibited the chondrogenesis, whereas STSN promoted the chondrogenesis in a dose dependent manner. In addition, PMA exerted no inhibitory effect when the cells were pretreated for 24 h with STSN, implying that the chondrogenic events might be settled at an early step in vitro and FKC may act as a negative modulator. Collectively, these results demonstrate, for the first time, the stage-related chondrogenic potential of human mandibular and limb bud mesenchyme cells and the role of PKC during chondrogenesis in vitro & in vivo.

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Induction of Apoptosis with Kigelia africana fruits in HCT116 Human Colon Cancer Cells via MAPKs Signaling Pathway

  • Guon, Tae-Eun;Chung, Ha Sook
    • Natural Product Sciences
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    • v.22 no.3
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    • pp.209-215
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    • 2016
  • Kigelia africana (Lam.) Benth. (Bignoniaceae) is a flowering plants in South, Central and West Africa and commonly known as the sausage tree (Eng.); worsboom (Afr.); umVunguta, umFongothi (Zulu); Modukguhlu (North Sotho); Muvevha (Venda). The dried, powdered fruits are used as dressing for wounds and ulcers, haemorrhoids, rheumatism, purgative, skin-firming, lactation in breast-feeding mothers. The aim of this study is to investigate the cytotoxic and apoptotic potentials of 70% ethanolic extracts of Kigelia africana fruits in HCT116 human colon cancer cells. Treatment of Kigelia africana fruits with various concentrations resulted in a sequence of characteristic of apoptosis, including loss of cell viability and morphological changes. Flow cytometry analysis showed Kigelia africana fruits increased the sub-G1 phase (apoptosis) population. Apoptosis confirmed by annexin V-fluorescein isothiocyanate and propidium iodide double staining in HCT116 human colon cancer cell lines. Moreover, analysis of the mechanism indicated that Kigelia africana fruits showed an increased Bax and Bcl-2 expressions in a dose-dependent manner, resulting in activation of hallmarks of apoptotic events, caspase-3, caspase-9 and cleaved poly-ADP-ribose polymerase. This is the first report to demonstrate the cytotoxicity of Kigelia africana fruits on HCT116 human colon cancer cells.

Ginsenoside-Rh2 Inhibits Proliferation and Induces Apoptosis of Human Gastric Cancer SGC-7901 Side Population Cells

  • Qian, Jun;Li, Jing;Jia, Jian-Guang;Jin, Xin;Yu, Da-Jun;Guo, Chen-Xu;Xie, Bo;Qian, Li-Yu
    • Asian Pacific Journal of Cancer Prevention
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    • v.17 no.4
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    • pp.1817-1821
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    • 2016
  • Objectives: To observed the effects of ginsenoside -Rh2 (GS-Rh2) on proliferation and apoptosis of side population (SP) human gastric cancer SGC-7901 cells. Materials and Methods: SGC-7901 SP and Non-SP cells were sorted by flow cytometry and assessed using the cck-8 method. Expression of apoptosis-related proteins Bax and Bcl-2 of SP before and after the intervention was determined by Western-blotting. Results: It was found that the proliferation of SP was significantly faster than that of NSP (P<0.05). In addition, GS-Rh2 inhibited proliferation of gastric cancer SP cells, induced cell cycle arrest and cell apoptosis, and changed the expression of BAX/Bcl-2 proteins in a time-dependent and concentration-dependent manner (P<0.05). Conclusions: With increase of GS-Rh2 dose, GS-Rh2 gradually inhibit the proliferation of SGC-7901 SP cells, which have high proliferation rate, through G1/G0 phase arrest, followed by apoptosis which involves the up-regulation of Bax and the down-regulation of Bcl-2.

In Pediatric Leukemia, Dose Evaluation according to the Type of Compensators in Total Body Irradiation (소아백혈병 환자의 전신방사선조사 시 조직보상체의 재질변화에 따른 선량평가)

  • Lee, Dongyeon;Kim, Changsoo;Kim, Junghoon
    • Journal of radiological science and technology
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    • v.38 no.1
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    • pp.17-21
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    • 2015
  • Total body irradiation(TBI) and chemotherapy are the pre-treatment method of a stem cell transplantations of the childhood leukemia. in this study, we evaluate the Quantitative human body dose prior to the treatment. The MCNPX simulation program evaluated by changing the material of the tissue compensators with imitation material of pediatric exposure in a virtual space. As a result, first, the average skin dose with the material of the tissue compensators of Plexiglass tissue compensators is 74.60 mGy/min, Al is 73.96 mGy/min, Cu is 72.26 mGy/min and Pb 67.90 mGy/min respectively. Second, regardless of the tissue compensators material that organ dose were thyroid, gentile, digestive system, brain, lungs, kidneys higher in order. Finally, the ideal distance between body compensator and the patient were 50 cm aparting each other. In conclusion, tissue compensators Al, Cu, Pb are able to replace of the currently used in Plexiglass materials.

Radio-Sensitization by Piper longumine of Human Breast Adenoma MDA-MB-231 Cells in Vitro

  • Yao, Jian-Xin;Yao, Zhi-Feng;Li, Zhan-Feng;Liu, Yong-Biao
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.7
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    • pp.3211-3217
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    • 2014
  • Background: The current study investigated the effects of Piper longumine on radio-sensitization of human breast cancer MDA-MB-231 cells and underlying mechanisms. Materials and Methods: Human breast cancer MDA-MB-231 cells were cultured in vitro and those in logarithmic growth phase were selected for experiments divided into four groups: control, X-ray exposed, Piper longumine, and Piper longumine combined with X-rays. Conogenic assays were performed to determine the radio-sensitizing effects. Cell survival curves were fitted by single-hit multi-target model and then the survival fraction (SF), average lethal dose ($D_0$), quasi-threshold dose ($D_q$) and sensitive enhancement ratio (SER) were calculated. Cell apoptosis was analyzed by flow cytometry (FCM). Western blot assays were employed for expression of apoptosis-related proteins (Bc1-2 and Bax) after treatment with Piper longumine and/or X-ray radiation. The intracellular reactive oxygen species (ROS) level was detected by FCM with a DCFH-DA probe. Results: The cloning formation capacity was decreased in the group of piperlongumine plus radiation, which displayed the values of SF2, D0, Dq significantly lower than those of radiation alone group and the sensitive enhancement ratio (SER) of D0 was1.22 and 1.29, respectively. The cell apoptosis rate was increased by the combination treatment of Piper longumine and radiation. Piper longumine increased the radiation-induced intracellular levels of ROS. Compared with the control group and individual group, the combination group demonstrated significantly decreased expression of Bcl-2 with increased Bax. Conclusions: Piper longumine at a non-cytotoxic concentration can enhance the radio-sensitivity of MDA-MB-231cells, which may be related to its regulation of apoptosis-related protein expression and the increase of intracellular ROS level, thus increasing radiation-induced apoptosis.